A thickening network of lipids

Piomelli, Daniele

doi:10.1016/j.pain.2011.09.026

Cited by 5 publications

(4 citation statements)

References 11 publications

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“…Neuropathic pain has been studied though genomic [27–29], proteomic [30, 31], and lipidomic [1, 32–34] approaches. Previous studies of neuropathic pain using lipidomic approach have mainly focused on PG which is rich in fatty acids and strongly contributes to the development of neuropathic pain [4].…”

Section: Discussionmentioning

confidence: 99%

Arachidonic acid containing phosphatidylcholine increases due to microglial activation in ipsilateral spinal dorsal horn following spared sciatic nerve injury

et al. 2017

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Peripheral nerve injury induces substantial molecular changes in the somatosensory system that leads to maladaptive plasticity and cause neuropathic pain. Understanding the molecular pathways responsible for the development of neuropathic pain is essential to the development of novel rationally designed therapeutics. Although lipids make up to half of the dry weight of the spinal cord, their relation with the development of neuropathic pain is poorly understood. We aimed to elucidate the regulation of spinal lipids in response to neuropathic peripheral nerve injury in mice by utilizing matrix-assisted laser desorption/ionization imaging mass spectrometry, which allows visualization of lipid distribution within the cord. We found that arachidonic acid (AA) containing

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Section: Discussionmentioning

confidence: 99%

Arachidonic acid containing phosphatidylcholine increases due to microglial activation in ipsilateral spinal dorsal horn following spared sciatic nerve injury

et al. 2017

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“…While cascades of protein kinases and phosphatases have been largely studied, there is an increasing interest in lipid-based pathways involving lipid kinases and phosphatases. Lipids are versatile in signal transduction pathways and act as hormones, ligands, substrates, and mediators (Eyster, 2007;Piomelli et al, 2007;Piomelli, 2012). Sphingolipids and cholesterol comprise lipid rafts, which are regions in the plasma membrane that organize signaling molecules, amplify intracellular signaling cascades, and regulate both neurotransmission and membrane protein trafficking (Levental and Veatch, 2016).…”

Section: Role Of Lipids In Neuronal Signalingmentioning

confidence: 99%

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

2020

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Lipids constitute the bulk of the dry mass of the brain and have been associated with healthy function as well as the most common pathological conditions of the brain. Demographic factors, genetics, and lifestyles are the major factors that influence lipid metabolism and are also the key components of lipid disruption in Alzheimer's disease (AD). Additionally, the most common genetic risk factor of AD, APOE 4 genotype, is involved in lipid transport and metabolism. We propose that lipids are at the center of Alzheimer's disease pathology based on their involvement in the blood-brain barrier function, amyloid precursor protein (APP) processing, myelination, membrane remodeling, receptor signaling, inflammation, oxidation, and energy balance. Under healthy conditions, lipid homeostasis bestows a balanced cellular environment that enables the proper functioning of brain cells. However, under pathological conditions, dyshomeostasis of brain lipid composition can result in disturbed BBB, abnormal processing of APP, dysfunction in endocytosis/exocytosis/autophagocytosis, altered myelination, disturbed signaling, unbalanced energy metabolism, and enhanced inflammation. These lipid disturbances may contribute to abnormalities in brain function that are the hallmark of AD. The wide variance of lipid disturbances associated with brain function suggest that AD pathology may present as a complex interaction between several metabolic pathways that are augmented by risk factors such as age, genetics, and lifestyles. Herewith, we examine factors that influence brain lipid composition, review the association of lipids with all known facets of AD pathology, and offer pointers for potential therapies that target lipid pathways.

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“…Fatty Acid Amide Hydrolase (FAAH) is an intracellular serine hydrolase responsible for the hydrolysis of a family of naturally occurring fatty-acid ethanolamides, which include endogenous agonists of cannabinoid receptors, such as anandamide (Figure ), − and peroxisome proliferator-activated receptor-α (PPAR-α), such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). − Pharmacological inhibition of FAAH activity magnifies and prolongs the biological actions of these lipid-derived messengers, offering a potential strategy to treat pathological conditions such as pain, addiction, and inflammation. − …”

Section: Introductionmentioning

confidence: 99%

Wagging the Tail: Essential Role of Substrate Flexibility in FAAH Catalysis

Palermo

Campomanes

Neri

et al. 2013

J. Chem. Theory Comput.

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The serine hydrolase, fatty acid amide hydrolase (FAAH), is responsible for the intracellular degradation of anandamide and other bioactive fatty acid ethanolamides involved in the regulation of pain, inflammation, and other pathophysiological processes. The catalytic site of FAAH is composed of multiple cavities with mixed hydrophobic and hydrophilic properties, the role of which remains incompletely understood. Anandamide is thought to enter the active site through a "membrane-access" (MA) channel and position its flexible fatty acyl chain in a highly hydrophobic "acyl chain-binding" (AB) cavity to allow for hydrolysis to occur. Using microsecond molecular dynamics (MD) simulations of FAAH embedded in a realistic membrane/water environment, we show now that anandamide may not lock itself into the AB cavity but may rather assume catalytically significant conformations required for hydrolysis by moving its flexible arachidonoyl tail between the MA and AB cavities. This process is regulated by a phenylalanine residue (Phe432) located at the boundary between the two cavities, which may act as a "dynamic paddle." The results identify structural flexibility as a key determinant by which FAAH recognizes its primary lipid substrate.

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A thickening network of lipids

Cited by 5 publications

References 11 publications

Arachidonic acid containing phosphatidylcholine increases due to microglial activation in ipsilateral spinal dorsal horn following spared sciatic nerve injury

Arachidonic acid containing phosphatidylcholine increases due to microglial activation in ipsilateral spinal dorsal horn following spared sciatic nerve injury

Involvement of Lipids in Alzheimer’s Disease Pathology and Potential Therapies

Wagging the Tail: Essential Role of Substrate Flexibility in FAAH Catalysis

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